Our long-term objective is to non-invasively detect atherosclerosis in its earliest stages, before symptomatic consequences occur, as well as to optimize spectral CT for ultimate clinical use. The goal of this proposal is to use photon-counting-detector-based spectral CT to provide the required spatial resolution and material discrimination sensitivity at much lower radiation doses than would be possible using integrating-detector- based conventional CT. The significance of achieving this goal is that effective treatment of the pathological mechanism(s) affecting the vascular wall, prior to irreversible consequences such as myocardial infarction or stroke, would be considerably more effective, and less expensive, at both the individual and societal levels. Further, our proposed studies will provide knowledge essential for reducing the radiation doses required in routine CT imaging and for other applications of spectral CT that require increased sensitivity for material discrimination . The innovation of this project lies in the use of a photon-counting-detector-based whole-body CT scanner to develop and validate the needed acquisition, reconstruction, and processing techniques. The rationale for using spectral CT is that it offers improved spatio-temporal resolution over other non-invasive methods, such as 3D MRI and radionuclide imaging, is less affected by partial volume averaging than conventional CT, and is capable of discriminating and quantifying the concentration of all relevant plaque components. Also, the effects of electronic noise on spectral CT using photon-counting detectors are negligible. This is important because breaking the x-ray spectrum into the small energy bins needed for improved material discrimination sensitivity drastically reduces the photon counts per bin. Further, noise reduction methods that exploit energy domain correlations can be used to increase the sensitivity to low concentrations of materials. Thus, increased radiation exposures will not be required. Use of narrow spectral energy bins also greatly reduces the local beam hardening effects due to arterial wall calcification and/or intraluminal contrast. The specific aims that wil enable us to achieve our goal are: AIM 1 - Develop optimized acquisition, reconstruction and processing techniques for whole-body spectral CT with photon-counting detector technology. We will fully characterize the spectral CT system; determine the optimal number, width and location of energy bins; implement and evaluate noise reduction algorithms and algorithms to discriminate and quantify the concentration of co-localized plaque components; and determine system accuracy and evaluate the impact of partial volume averaging. AIM 2 - Determine the sensitivity and specificity of whole-body spectral CT for the identification of atherosclerotic plaque components in human cadavers. AIM 3 - In anesthetized pigs, quantify neovascularization in major arterial walls, as an early indicator of atherosclerotic plaque formation, using iodine-based contrast agents.